The Caliciviridae is a family of positive-strand RNA viruses and consists of five genera designated: (1) Norovirus (with species Norwalk virus); (2) Sapovirus (with species Sapporo virus); (3) Vesivirus (with species, feline calicivirus and vesicular exanthema of swine virus); (4) Lagovirus (with species rabbit hemorrhagic disease virus and European brown hare syndrome virus) and (5) Nebovirus (with species Newbury-2 virus). The Caliciviruses Section in LID is focused on one major goal: lessen the disease burden from caliciviruses that cause disease in humans. Noroviruses are the primary focus of our research because they are the major calicivirus pathogens in humans. They cause the majority of epidemic gastroenteritis outbreaks and are second to rotaviruses as agents of severe diarrhea in infants and young children. They can cause chronic infection and life-threatening illness in immunocompromised individuals. Noroviruses are genetically-diverse and most human norovirus pathogens belong to either Genogroup I (GI) or Genogroup II (GII), with GII.4 as the predominant genotype. Because a major technical challenge in the study of these viruses is the inability to grow them in cultured cells, our laboratory has developed calicivirus replication systems and animal models to establish parameters of infection and immunity. We discontinued our norovirus studies in chimpanzees this year, and are aiming now to develop new animal models and in vitro systems in which to evaluate norovirus vaccines and therapeutic drugs. To facilitate progress in these areas, we have established collaboration with clinical investigators within and outside NIH. We are collaborating with a leading company in norovirus vaccine development, Takeda Vaccines Montana (formerly LigoCyte Pharmaceuticals, Inc.), to address the immunogenicity and broad reactivity of new norovirus vaccine candidates. One approach under consideration for the treatment of norovirus disease is therapeutic antibodies, and we have made progress in this area. In collaboration with Dr. Robert H. Purcell (LID), we generated the first norovirus-specific antibodies with putative neutralizing activity as demonstrated in the chimpanzee model before the model was discontinued (see scientific advance below). We are continuing to develop and map additional antibodies in the laboratory, generated by a variety of technologies including nanobody technology in collaboration with Dr. Viviana Parreo at INTA in Argentina. One goal is to map cross-reactive antigenic sites that might serve as targets for the design of broadly-protective vaccines, and this year we published the characterization of the first known antibody that reacts across all strains in the genus Norovirus. We have identified also human norovirus epitopes that are transferable to different protein or live virus backgrounds, offering promise that such epitopes could be expressed and characterized in the absence of a cell culture system for the human noroviruses. Archival samples have been continued to be invaluable in our antibody mapping studies that search for potent neutralizing epitopes that are conserved over time.